Although lithium displays remarkable mood-stabilizing properties and has served as one of the most effective therapies for bipolar disorder (BPD), the mechanisms underlying its actions on the nervous system remain unclear. The long-term goal of this project is to understand-at the molecular and cellular levels-how lithium affects nervous system function. The objectives of this proposal are to identify genes that are involved in the lithium-responsive neurological process and to determine their roles in lithium's therapeutic action. To accomplish these objectives, we will utilize genetic tools that are uniquely available in the fruit fly Drosophila melanogaster. These include a neurological mutant Shudderer (Shu), whose phenotypes are largely rescued by lithium administration at therapeutic concentrations. Our central hypothesis, which is based on strong preliminary data, is that lithium reduces the severity of neurological defects caused by up-regulation of the Ca2????dependent phosphatase calcineurin, and that it does so by suppressing the innate immune response. The rationale for the proposed research is that, once the genes involved in lithium-responsive neurological processes in Drosophila have been identified and their roles have been revealed, this information should be readily translated into the vertebrate system, which is known to use signaling mechanisms that overlap extensively with those in Drosophila. Thus, our study is expected to provide novel and important insights into lithium's therapeutic action-with respect not only to BPD, but also other neurological disorders. Our central hypothesis will be tested by pursuing three specific aims: 1) Determine how up-regulation of calcineurin causes the lithium-responsive neurological defects; 2) Delineate the mechanisms responsible for lithium's therapeutic action on the Shu phenotype; and 3) Identify novel genes whose up- or down-regulation mimics lithium's actions in the nervous system. For the first aim, particular cell types and developmental timing of the calcineurin overexpression leading to the Shu phenotype will be defined by genetically manipulating calcineurin activity in a spatially and temporally specific manner. For the second aim, various genetic variants will be utilized to determine the extent to which the innate immune system is involved in manifestation of lithium-responsive neurological defects. For the third aim, molecularly defined mutants and RNAi will be employed to confirm the involvement of novel genes (from candidates that have been identified in genome-wide screens) in the lithium-responsive neurological processes. The proposed research is innovative in that it capitalizes on the power of Drosophila genetics to identify and characterize genes that are involved in lithium's actions in the nervous system. The proposed research is significant because it is expected to lead to the recognition of molecules and molecular interactions that are responsible for lithium's actions in the vertebrate nervous system. This would open up new avenues toward a better understanding of the etiology and pathophysiology of BPD, and result in improved therapies for BPD and other disorders of the nervous system. PUBLIC HEALTH RELEVANCE: The proposed studies aim at understanding the evolutionarily conserved neurological processes that are affected by lithium. This research is of high relevance to public health because lithium is an effective drug for the treatment of mood disorders, as well as potentially being useful for the treatment or prevention of brain damage. Thus, the findings are expected to contribute to significant future improvements in human health.